This invention relates to a method of bone cement preparation. It further relates to a bone cement mixture obtained by said method and an apparatus for performing said method.
The invention allows for preparation of a pore-free, mechanically superior bone cement, in a closed system that requires minimal human intervention, and delivers a consistent, operator-independent performance.
Surgical bone cement is commonly used for fixation of joint prosthesis, most frequently in total hip and total knee replacement. It is prepared by mixing a powder component, comprising emulsion polymerized polymethylmethacrylate (PMMA), with a methyl-methacrylate (MMA)-based liquid. The conventional catalytic system for the room temperature curing resins is based on the chemical decomposition of benzoyl peroxide by an accelerator, N,N-dimethyl-p-toluidine. Decomposition of benzoyl peroxide releases free (phenyl) radicals and initiates polymerization of MMA. Benzoyl peroxide is either residual, i.e. left over from the polymerization of the PMMA powder, or is added in powder form to PMMA. The accelerator is added to MMA liquid, which, at the least, also contains radical scavenger hydroquinone to prevent accidental polymerization.
In conventional bone cements, introduced to total hip replacement (THR) surgery by Dr. John Charnley in the early sixties, the powder and the liquid components are mixed together, either by a spatula in a simple bowl, or in dedicated mixing/delivery devices. Increase in the clinical use of dedicated mixing devices has been driven by mostly two factors: (i) hand mixing in open air leads to air bubble inclusions which significantly reduce the strength of bone cement; (ii) undesirable exposure of the operating room personnel to monomer vapours. Pores within the bone cement mantle, caused mostly by inclusion of air bubbles during mixing, reduce its fatigue strength, which is now generally accepted to be a major risk factor in aseptic loosening of cemented prosthetic components.
Mixing of the powder and the liquid aims at full wetting of the powder, i.e. all beads should be surrounded by the liquid. Upon decomposition of benzoyl peroxide and release of free radicals, monomer polymerizes with nucleation on the partially dissolved surface of the beads. The amount of monomer relative to powder is thus determined by predominantly physical, rather than chemical considerations. Three characteristics of polymerization effect the outcome and set the limitations on the possible improvements. Polymerization is:
(i) exothermic:
polymerization of MMA into PMMA releases a fixed amount of heat per mole (55,6 kJ/mol). Release of polymerization heat could increase the temperature of the bone cement mixture by more than 100 deg C, but due to heat transfer into surrounding tissues and the prosthesis, temperatures at the interface to bone rarely exceed 60 deg C. The ratio of monomer to polymer is an important factor influencing final temperature increase. Less monomer to polymerize means less heat released, and the more polymer there is to warm up, the lower the temperature. Bone cement according to this invention uses about 20% less monomer than conventional hand mixing formulations, which results in reduced peak temperatures (by about 8 degrees C).
(ii) density increasing:
density of MMA monomer is 943 kg/m3, density of the polymer is 1180 kg/m3, i.e. polymerization is associated with volumetric shrinkage of about 20%. With a typical ratio of polymer to monomer of 2,1:1, this leads to an expected cured cement shrinkage of about 6,5%. However, the ultimate, experimentally measurable, volumetric shrinkage depends on other factors, most importantly on the amount of pores within the cement. Presence of pores allows for shrinkage to be compensated from within, i.e. the pores get larger and the volume change measured from outside is less than if the cement were pore-free. In general, all methods deployed to reduce cement porosity lead to an increase in shrinkage. Reduced use of monomer in the cement of this invention is of an advantage here as well; about 1% less shrinkage is expected, other factors (i.e. cement and sample preparation technique) being the same.
(iii) incomplete:
polymerization process depends on formation of free radicals to initiate it, nucleation on the extant polymer surfaces and availability of monomer molecules to extend the growing chains. In all cases, a number of monomer molecules will not find their way into polymer chains and will thus remain as residual monomer within the polymerized matrix. Polymerization process will continue at a very limited rate even after most of the polymer matrix is formed due to mobility of monomer molecules through the polymerized matrix. That same mobility allows monomer to leach out of the cured cement. This is deemed undesirable in view of tissue compatibility. The range of residual monomer found in commercial cements right after preparation is about 2 to 6% (monomer weight per total weight). In time (with quasiequilibrium reached in 2 to 4 weeks) this is reduced to less than 0,5% due to combined effects of continuing polymerization, migration and release of free monomer. Again, reduced use of monomer in the cement of this invention is of an advantage here as well; less monomer to start with leads to a lower residue (about 20% compared to the best selling regular viscosity cement).
In the early eighties the shortcomings of hand mixing and delivery of bone cement became widely acknowledged. With the first long term studies of improved cementing techniques becoming available, showing better clinical results than traditional hand mixing/hand application, the interest for, and clinical use of various systems for bone cement preparation has been steadily increasing. Disappointments with the clinical outcomes of cementless prosthesis have also contributed to re-establishment of cemented total joint replacement as a standard procedure, especially for the femoral component of the total hip replacement and for total knee prosthesis.
All known, commercially available and clinically used mixing systems are designed to remove air inclusions which are invariably introduced at the time when the liquid and powdered components are brought into contact. This task can only be partially accomplished due to mostly time limitations imposed by dissolution of PMMA in MMA and kinetics of polymerization.
Centrifuging:
Championed by Dr. William Harris, Boston, centrifuging was found to be partially effective in reducing the porosity of certain commercial brands of bone cement. While centrifuging could be used with some of the existing cements, it required cumbersome equipment, chilling of cement (to reduce viscosity and prolong setting time) and tight coordination of operating room personnel. It has found rather limited clinical acceptance in the U.S. and even less in Europe. The use of the bottom-up filling technique for the femur by means of a caulking gun, syringe and a long nozzle, as well as pre-plugging of the femoral canal to allow for cement pressurizing have also been introduced by Dr. Harris. Currently, both, the older top-down and the bottom-up filling technique are used in Europe; in the U.S. the latter is dominant.
Partial Vacuum Mixing:
Developed and brought into clinical use by Dr. Lars Lidgren, Lund, this technique was adopted from the dental field where the same materials have been used for decades before introduction into orthopaedics. In molding of dentures from MMA/PMMA resins, air entrapment has also been recognized as undesirable; here less for reduction of strength than for difficulties of hygiene maintenance in dentures with pores which may be open to the surface. Mixing the cement in a bowl under partial vacuum (of some 100 mbar) reduces the porosity of the material cured at atmospheric, or elevated pressure. Partial vacuum mixing systems have found the widest clinical acceptance. Regular viscosity cements, such as Palacos R, are usually chilled (to reduce viscosity and prolong the setting time) for preparation in these systems and for extrusion through the nozzle in bottom-up delivery.
Laboratory tests show improved fatigue properties of partial vacuum mixed cements, but clinical long term studies do not support expectations. The reasons for this are obscure at the moment, but there are indications that the learning curve in the widespread use of partial vacuum mixing systems may explain this discrepancy; surgery departments that have used such systems for longer times show better outcomes than the newcomers.
Pre-pressurizing:
Developed by Dr. K. Draenert, Munich, pre-pressurizing of the bone cement aims at reducing porosity by prolonged application of pressure onto the mixed cement. While the pores are reduced during the application of pressure within the syringe, most of the effect is lost upon extrusion of the cement into the bone, where it cannot be substantially pressurized. Some benefit could be expected due to expansion of pressurized air within the pores in terms of compensating for the polymerization shrinkage, but this is very much subject to timing and viscosity of the cement. Overall, pre-pressurizing is probably the least effective measure for porosity reduction (even in laboratory tests done under optimal conditions). Dr. Draenart has subsequently expanded his original system to incorporate partial vacuum mixing, as well as pre-pressurizing.
Clinical practice, is dominated by various systems for partial vacuum mixing. The basic limitation is imposed by the level of vacuum under which mixing can be carried out. At room temperature, MMA monomer will boil at 38 mbar. Most systems are designed to operate at about 100 mbar. This leaves a significant amount of residual air entrapped in the mixed cement; once the mixture is brought back to atmospheric pressure, air inclusions shrink, say by factor 10 to 20, but pores in fact do persistxe2x80x94they are only reduced in size. This improves mechanical properties, including fatigue strength, but mostly by the increase in the effective cross section and less by reduction in stress concentration which is not so much influenced by the size of pores.
From W088/03811 TEPIC a vacuum flooding system is known which is essentially free of air inclusions, but the requirement for high vacuum in that system is technically difficult to achieve.
Following the basic principles of the method according to the present inventionxe2x80x94vacuum-induced flooding of the powder and draining of excess liquidxe2x80x94are described in detail. In contrast to other known bone cement preparation systems, the present invention aims at avoiding inclusion of air, rather than allowing for it, and then reducing it. This is accomplished by pre-packing the powder into a syringe, and then drawing the liquid through the powder column by vacuum. As the fluid moves into the powder column residual air in front of the flooding front is pulled away by the vacuum. The end result is that the residual air between the particles of powder is replaced by the cement liquid. The process leads to full wetting contact between the beads and the liquid, rendering any mechanical mixing superfluous.
Because of high solubility of benzoyl peroxide in MMA, benzoyl peroxide should preferably not be added in powdered form. Flooding of powder would result in a gradient of catalyst and lead to uneven polymerization. However, emulsion polymerized PMMA powders can be produced with residue of benzoyl peroxide which upon dissolution of the surface layer of the beads becomes available for the reaction with toluidine. Use of such powders with sufficient residue of benzoyl peroxide (with an average value in the range of 1,0% to 2,5%) allows for flooding of a packed powder column with only a slight gradient in concentrations of the catalytic system components.
Deployment of vacuum-induced, controlled flooding eliminates the need for mixing, and removes a major source of variability in cement preparation. Solubility of the PMMA powder leads to additional packing (consolidation) of the column after flooding, which creates a small excess of monomer at the inlet side of the syringe. This excess is expelled (back into the ampoule) by the action of a pneumatically driven piston before the cement syringe is removed from the vacuum pump and placed on the caulking gun for extrusion. Since the syringe ports for vacuum and liquid are provided with screens which do not allow any loss of powder, the action of the pneumatic piston leads to draining of the cement mixture (from any excess monomer). This also provides for the reduced ultimate content of monomer (by about 20%), which in other mixed cements must be present in excess in order to allow for better wetting.
Besides methylmethacrylate other suitable polymerisable monomers or comonomers may be used as e.g. ethyl-methacrylate or butyl-methacrylate or mixtures of such methacrylates.
The vacuum source should be able to generate a vacuum in the range of 10 to 200 mbar, preferably in the range of 50 to 100 mbar.